This analysis was performed to fill gaps in clinical evidence from RCTs on visual outcomes and treatment burden of anti-VEGF T&E therapies in a 2-year perspective. The NMA was performed using six RCTs (ALTAIR, VIEW 1 and 2, CATT, CANTREAT, and TREX). The results of this comparison indicate that over 2 years, IVT-AFL T&E provided visual improvements comparable to those achieved with RBZ T&E with a lower treatment burden based on significantly fewer injections.
The pivotal ALTAIR trial assessing two different regimens of IVT-AFL T&E regimens could not be connected within a network of evidence with the remaining trials assessing anti-VEGF regimen, which precluded the possibility of using standard network meta-analysis to compare between IVT-AFL T&E and RBZ T&E. Therefore, we followed the guidelines issued by the NICE Decision Support Unit describing methods for the population-adjusted indirect comparison between disconnected evidence and incomplete networks . In this analysis we conducted MAIC and adopted regression-based analysis to reconstitute the connection of incomplete networks of evidence allowing one to compare between IVT-AF T&E versus RBZ T&E.
Clinical data comparing the efficacy and treatment burden of IVT-AFL and RBZ in a longer perspective are limited. Results of an NMA reported by Danyliv et al. did not demonstrate significant differences between IVT-AFL fixed regimens versus various RBZ regimens regarding visual outcomes . The estimates presented by Danyliv et al. were based on the two large RCTs (VIEW 1 and 2) designed to compare IVT-AFL versus RBZ [27, 31]. During the first year, patients received intravitreal injections of RBZ every 4 weeks or IVT-AFL every 4 weeks or every 8 weeks after three initial monthly injections. During the second year, patients continued to receive their originally assigned agents. While patients were followed up every 4 weeks and could receive injections at follow-up visits, based on protocol-defined retreatment criteria, only quarterly injections were mandatory. The results of VIEW trials indicate that IVT-AFL 2 mg monthly and RBZ 0.5 mg monthly were equally effective and had comparable safety profiles at 1 year and 2 years, despite that approximately five fewer doses were administered in the 2 mg monthly IVT-AFL group throughout the entire follow-up (16.0 vs 11.2 injections) [27, 31].
Although the VIEW trials demonstrate that IVT-AFL yields visual effects similar to those seen with RBZ, with a lower number of injections, it was not immediately understood how those findings could be extrapolated to T&E regimens . While the RIVAL study is the only clinical trial comparing IVT-AFL and RBZ in an identical proactive treatment regimen, described as T&E, the treatment criteria were geared towards aggressive elimination of any retinal fluid in order to achieve its primary endpoint. This study had been designed to assess treatment differences regarding the change in the area of geographic atrophy from baseline to 24 months as the primary outcome measures. Visual outcomes and the number of injections at 12 and 24 months were defined as secondary objectives. Since the statistical analysis did not adjust for multiple comparisons, the reported estimates should be interpreted with caution. The recently published results from the RIVAL study reported similar mean BCVA gain in IVT-AFL and RBZ groups at 12 months (+ 5.2 vs + 6.9 logMAR letters) and 24 months (+ 5.3 vs + 6.5 logMAR letters) [17, 18]. In the first year, patients received on average 9.7 injections in each group, while over entire 2-year treatment period the mean number of injections was 17.0 and 17.7 in IVT-AFL and RBZ arms, respectively. The external validity of these estimates is questionable not only because of the study design limitation related to primary outcome and statistical analysis but also owing to concerns regarding assessed treatment regimens. All patients received allocated therapies according to the same regimen of three initial monthly doses followed by an extension phase, during which the interval between subsequent injections was adjusted by 2 weeks within a range of a minimum of 4 weeks and a maximum of 12 weeks between administrations. Additionally, the between-treatment interval was shortened to 4 weeks if more than one sign of disease activity was observed, thus limiting the number of possible extensions. The schedule adopted in RIVAL required more frequent IVT-AFL administration compared with the European label for IVT-AFL, which indicates that—after the 3 initial monthly injections, the interval between subsequent IVT-AFL injections should not be shorter than 8 weeks. As a result, patients treated with IVT AFL in the RIVAL study received more intensive treatment than has been described in the ALTAIR trial assessing IVT-AFL regimens (17 injections vs 10.4 injections at 104 and 96 weeks, respectively) and combined IVT-AFL Q8W arms from the VIEW 1 and 2 trials (17 injections vs 11.2 injections at 104 and 96 weeks, respectively), which may constitute overtreatment. Importantly, the pooled results of the VIEW 1 and 2 trials indicate that additional injections with IVT-AFL do not yield additional clinical benefit . Therefore an injection of IVT-AFL when not clinically indicated might not improve its efficacy compared with RBZ T&E but potentially jeopardized the between-treatment comparison regarding the mean number of injections. A more intensive intravitreal regimen may be considered justified to treat patients with suboptimal response during the treatment. For example, the presence of PCV has been considered as a potential predictor of poor response of patients with wAMD treated with anti-VEGF regimens [32,33,34]. Approved IVT-AFL T&E regimen may not be sufficient to treat non-responders with PCV, who may require more frequent anti-VEGF injections and the use of rescue photodynamic therapy. As demonstrated in the PLANET trial, around 12.1% of participants with PCV required monthly IVT-AFL T&E combined with rescue photodynamic therapy within the first year of treatment . Taking into account that the RIVAL trial recruited predominantly white patients with low baseline risk of PCV, it seems unlikely that more intensive administration of IVT-AFL T&E could be attributed to PCV-related non-responders. Therefore, owing to the serious methodological concerns and limited external validity, the RIVAL trial was excluded from our analysis.
The IVT-AFL T&E regimen has been granted market authorization in the EU, Australia, and Japan on the basis of the outcomes of the ALTAIR study. This study demonstrated the efficacy and treatment burden of two different approaches of IVT-AFL T&E dosing with a 2-week and 4-week adjustment. At 2 years, patients receiving IVT-AFL T&E improved their visual acuity by 6.1–7.6 ETDRS letters with 10.4 injections compared with baseline. The evidence from RCTs on the use of RBZ T&E at 2 years is also limited. Two ongoing studies met the inclusion criteria for this analysis: the CANTREAT trial and small TREX-AMD study. A naive unadjusted comparison of the results from these studies indicate that RBZ T&E provides visual improvement similar to that achieved using IVT-AFL T&E (6.4 ETDRS letter gain in CANTREAT and 8.7 in TREX), but with a higher absolute number of injections (18.0 in CANTREAT and 18.6 in TREX). These results are consistent with the LUCAS trial, which was not included in this analysis because it did not meet the inclusion criteria (assessment of an off-label therapy as comparator), in which at 2 years, patients allocated to the RBZ T&E arm received a mean number of 16.0 intravitreal injections, which was associated with a 6.6 ETDRS letter gain compared with baseline .
The current NMA has some limitations: first, the connection between the ALTAIR study and the network was reconstituted using methods for an unanchored comparison, which allows adjustments only for a few treatment modifiers in each analysis. Second, standard deviations were not published in all studies assessing RBZ regimens and had to be imputed to conduct NMA. Third, the proportion of patients with PCV at baseline was available only for the ALTAIR trial and had to be estimated for the remaining trials in order to allow for PCV-adjusted analysis. The estimation of the percentage of patients with PCV was based on the results of epidemiologic meta-analysis, including 11 studies identified through SLR . This estimation is associated with inherent uncertainty, since the prevalence of PCV in studies included in this ITC could differ from the point estimate reported in the meta-analysis. Although there was a tentative estimation of the proportion of PCV, populations enrolled in different studies may vary. For these reasons, the estimates adjusted for PCV should be interpreted with caution. However, the sensitivity analyses demonstrated that the adjustment for baseline PCV may not change the inference of this comparison. The results of all the analyses consistently did not reveal any significant differences between IVT-AFL T&E and RBZ regarding visual acuity gain and demonstrated a noticeably lower number of injections in IVT-AFL T&E group. Models adjusting for baseline PCV slightly favored IVT-AFL T&E in terms of visual acuity compared with models not accounting for PCV although without change of the inference. On the contrary, the estimates for the treatment burden were highly consistent across all sensitivity analyses with or without baseline PCV as a covariate. This is because no interaction between the presence of PCV and injection frequency was observed in the ALTAIR trial.
Fourth, there was a slight discrepancy between trials regarding the exact time point of the data collection for the analysis at 2 years. The data for the IVT-AFL T&E were collected 8 weeks earlier compared with the data for RBZ T&E (96 weeks vs 104 weeks), which may slightly interfere with the comparison between IVT-AFL T&E and RBZ T&E regarding the number of injections. However, the impact of this 8-week difference is limited because of the low frequency of IVT-AFL T&E administration in the second year of the ALTAIR trial (3.7 injections administered between week 54 and week 96). On the basis of this information, it can be assumed that patients would receive less than one additional AFL injection if ALTAIR were extended to 104 weeks. This means that at 104 weeks, IVT-AFL T&E is associated with an estimated five fewer injections compared with RBZ T&E. Finally, the included studies assessing T&E regimens differed regarding the time when the extension was initiated and the possible ranges of injection intervals. It cannot be excluded that the between-study differences regarding T&E posology may, in part, explain the difference in the number of injections between IVT-AFL T&E and RBZ T&E estimated in this analysis.
Administration of anti-VEGF therapy imposes a serious burden on patients due to treatment-related anxiety, financial considerations, and transport burden . Most patients with wAMD have varying degrees of disability due to age and insufficient vision, and thus require help in their daily activities as well as escorts when travelling to the hospital [38, 39]. The disease itself and the treatment frequency are therefore associated with a significant caregiver burden, which can have a negative impact on the relationships between the caregiver and patient [38, 40]. The frequency of injections can be considered a relevant surrogate of a treatment burden. Therefore, the results of our comparison indicate that IVT-AFL T&E may serve as an optimal treatment option, owing to its clinical efficacy, which is comparable to that of RBZ T&E, and a noticeably lower treatment burden .
The between-treatment difference in the number of injections is consistent with individual RCT results and reflects differences in the T&E regimens tested and criteria for extension adopted in respective studies. In the ALTAIR trial, IVT-AFL T&E was administered at weeks 0, 4, 8, and 16, followed by the variable treatment interval ranging from 8 to 16 weeks. The interval was adjusted on the basis of physician judgment of vision and/or anatomic outcomes. On the contrary, RBZ T&E monthly treatment could be continued following initial doses (1) until (in the CANTREAT study) visual acuity was deemed stable, indicated by an improvement in visual acuity of at most 3 ETDRS letters gained (or no loss of more than 5 letters) from the prior month; no clinical evidence of lesion growth, fluid, or blood; and no intraretinal or subretinal fluid seen on optical coherence tomography; or (2) until (in the TREX study) achievement of “dry” retina based on resolution of intraretinal and subretinal fluid and all subretinal hemorrhage related to active wAMD. When this was achieved, the treatment interval could be extended by 2 weeks to a maximum of 12 weeks. In the case of recurrent disease activity, the between-injection interval could be shortened to a minimum of 4 weeks.
Finally, this analysis was based on RCTs conducted under experimental conditions with tightly defined treatment algorithms, which might not fully reflect the posology used in real clinical practice. Therefore, the differences in relative efficacy and treatment burden between IVT-AFL T&E and RBZ T&E administered in the real-world settings may potentially differ from the estimates of this analysis.